Natural killer (NK) cells are a subset of large granular lymphocytes that act as cytotoxic immune cells. The cytotoxic activity mediated by NK cells naturally against target cells (e.g., cancer cells, virally infected cells) is generally expressed a being the result of a “balance” of positive and negative signals transmitted respectively by activating and inhibitory cell surface receptors.
NK cells can be identified by any number of known cell surface markers which vary between species (e.g., in humans CD56, CD16, NKp44, NKp46, and NKp30 are often used; in mice NK1.1, Ly49A-W, CD49b are often used). In an active state, NK cells are capable of killing certain autologous, allogeneic, and even xenogeneic tumor cells, virus-infected cells, certain bacteria (e.g., Salmonella typhi), and other target cells. NK cells appear to preferentially kill target cells that express little or no Major Histocompatibility Class I (“MHCI” or “MHC-I”) molecules on their surface. NK cells also kill target cells to which antibody molecules have attached, a mechanism known as antibody-dependent cellular cytotoxicity (ADCC). In action against target cells, NK cells can release pore-forming proteins called perforins, proteolytic enzymes called granzymes, and cytokines/chemokines (e.g., TNFα, IFNγ, etc.) that directly lead to target cell apoptosis or lysis, or that regulate other immune responses. Upon activation, NK cells also may express Fas ligand (FasL), enabling these cells to induce apoptosis in cells that express Fas.
Sufficient NK cell activity and NK cell count typically are both necessary to mounting an adequate NK cell-mediated immune response. NK cells may be present in normal numbers in an individual, but if not activated these cells will be ineffective in performing vital immune system functions, such as eliminating abnormal cells. Decreased NK cell activity is linked to the development and progression of many diseases. For example, research has demonstrated that low NK cell activity causes greater susceptibility to diseases such as chronic fatigue syndrome (CFS), viral infections, and the development of cancers.
NK cell activity is regulated by NK cell activity-modulating receptors (“NKCAMRs” or simply “AMRs”), which may be specific for various ligands such as MHC-I molecules, MHC-I homologs, or other biological molecules expressed on target cells. NK cells in an individual typically present a number of activating and inhibitory receptors. The activity of NK cells is regulated by a balance of signals transduced through these activating and inhibitory receptors. Each type of NKCAMR is briefly discussed in turn below. Most NKCAMRs appear to belong to one of two classes of proteins: the immunoglobulin (Ig)-like receptor superfamily (IgSF) or the C-type lectin-like receptor (CTLR) super family (see, e.g., Radaev and Sun, Annu. Rev. Biomol. Struct. 2003 32:93-114). However, other forms of NKCAMRs are known.
Antibodies against NKCAMR, such as killer immunoglobulin-like receptors (KIR), have been previously described and there also has been at least some suggestion of combining anti-NK receptor antibodies, such as anti-KIR antibodies, with other anti-cancer agents in the prior art. For example, WO2004056392 describes anti-NKp30 and/or anti-NKp46 antibodies used in admixture with interleukin-2 (IL-2). WO2005009465 describes the combination of a therapeutic antibody (e.g., Rituxan) in combination with a compound that blocks an inhibitory receptor or stimulates an activating receptor of an NK cell (e.g., an anti-KIR mAb, such as the mAb DF200, or an anti-NKp30 mAb) in order to enhance the efficiency of the treatment with therapeutic antibodies in human subjects (see also US 20050037002). WO2008/084106 describes anti-KIR formulations, dosages and dose regimens. WO2005079766 also describes combinations of antibodies (e.g., anti-tissue factor antibodies) including anti-KIR antibodies for use in cancer therapies. WO2005003168 and WO2005003172 describe combinations of a number of anti-KIR antibodies with a variety of agents, including IL-2 and IL-21. WO2005037306 similarly describes combinations of IL-21, IL-21 derivatives, and IL-21 analogues in combination with anti-KIR antibodies.
While NK cells have received a great deal of attention in the scientific literature for their potential contribution to anti-tumor responses mediated by antibodies that bind tumor antigens, few studies have been directed to examining the in vivo efficacy or potentiating NK cell cytotoxicity directly by modulating NK cell receptors. Treatments with NK cell modulating compounds have to date generally been envisaged as potentially restoring the ability of NK cells to kill target cells. Such treatments have not been used in patients without advanced disease, possibly in view of evidence that NK cell immunosurveillance is impaired with significant disease (e.g., tumor burden). For example, in myeloma, aggressive multiple myeloma (MM) parallels with a quantitative decline and functional exhaustion of NK cells. NK cell count also declines and NK cells become hyporesponsive to stimulation in patients with advanced MM.
Consequently, there is a need in the art for methods of using NK cell modulation to provide improved benefit to patients. Compounds that modulate NK cell activity, e.g., anti-+NKCIR antibodies and fragments thereof, may be particularly useful in the treatment of cancer.